RAGE–NFκB–SHP-2 Signaling Drives Monocyte Hyperactivation in Type 2 Diabetes: A Novel Target to Prevent Atherogenesis and Improve Surgical Outcomes

All articles of this category (opens in new window) Background: In T2DM, hyperactive monocytes accelerate atherogenesis and substantially increase the risk of adverse outcomes after cardiovascular surgery. While SHP-2 tyrosine phosphatase drives VEGF resistance in diabetic monocytes, its upstream remained unclear. We investigated how AGE–RAGE signaling, NFκB, AP1, and ROS regulate SHP-2 expression and monocyte migration in a diabetic milieu to identify potential perioperative interventions. Methods: Primary human monocytes from T2DM patients ( n = 12) and controls ( n = 12), plus murine db/db monocytes, were analyzed. Cells were treated with 300 µM methylglyoxal (MG), 150 µg/mL AGE-BSA, or 10 µg/mL TNFα, with/without NFκB inhibitors (NFκBi I, JSH23), AP1 inhibitor (SR 11302), ROS scavengers (PEG-catalase, VAS2870), RAGE antagonists (FPS-ZM1, RAGE peptide), or SHP-2 inhibitors (SHP099, NSC-878777). EMSA assessed transcription factor binding; transwell assays measured monocyte migration. Surface receptor levels were quantified by flow cytometry to validate expression changes. Statistical analyses used Mann–Whitney or Kruskal–Wallis tests. Results: T2DM monocytes showed elevated SHP-2 and RAGE expression with enhanced migration vs. controls. MG and AGE-BSA substantially increased SHP-2 through RAGE-dependent NFκB activation, confirmed by EMSA demonstrating NFκB-p65 binding to the PTPN11 promoter. Despite both NFκB and AP1 binding sites in the promoter, AP1 inhibition did not alter MG-induced SHP-2 upregulation. Similarly, ROS scavenging failed to influence SHP-2 responses, establishing NFκB as the key pathway. Complete blockade of RAGE or SHP-2 normalizes monocyte activity and restores migration patterns to control levels. Interestingly, monocytes from patients with higher TNFα express much more SHP-2, and diabetic patients with poor glycemic control showed enhanced SHP-2 responses, confirming that better glucose management might help control this pathway. Flow cytometry showed that diabetic monocytes expressed 2.3-fold higher surface RAGE than nondiabetic monocytes. Conclusion: The RAGE–NFκB–SHP-2 signaling axis constitutes a fundamental mechanism underlying diabetic vascular pathology with direct surgical relevance. Unlike AP1 and ROS pathways, this axis provides specific therapeutic targets for reducing monocyte-driven inflammation before and after vascular procedures. Strategic RAGE or NFκB targeting may improve surgical outcomes by diminishing monocyte activation, potentially reducing restenosis rates, and enhancing graft patency in T2DM patients requiring cardiovascular interventions. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany